Pyridil carboxamides as 5HT2B/2C receptor antagonists

ABSTRACT

Novel heterocyclic compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders are disclosed.

This invention relates to compounds having pharmacological activity,processes for their preparation, to compositions containing them and totheir use in the treatment of CNS disorders.

WO 92/05170, WO 94/04533, WO 94/14801, WO 95/01976 and J. Med. Chem.,1995, 38, 2524-2530 (SmithKline Beecham plc) describe indole andindoline derivatives which are described as possessing 5HT_(2C) receptorantagonist activity. Indole-3-carboxylic acid compounds having 5HT₃antagonist activity are diclosed in JPA 03 161 470. Indole derivativeshaving activity as tyrosine kinase inhibitors are disclosed in J. Med.Chem., 1995, 38, 58-57. Quinoline and indoline derivatives havingpotassium channel activating activity are disclosed in EPA 0 610 553 (E.R. Squibb).

A structurally distinct class of compounds has now been discovered,which have been found to have 5HT_(2C) receptor antagonist activity.Certain compounds of the invention also exhibit 5HT_(2B) antagonistactivity. 5HT_(2C/2B) receptor antagonists are believed to be ofpotential use in the treatment of CNS disorders such as anxiety,depression, epilepsy, obsessive compulsive disorders, migraine,Alzheimers disease, sleep disorders, feeding disorders such as anorexiaand bulimia, panic attacks, withdrawal from drug abuse such as cocaine,ethanol, nicotine and benzodiazepines, schizophrenia, and also disordersassociated with spinal trauma and/or head injury such as hydrocephalus.Compounds of the invention are also expected to be of use in thetreatment of certain GI disorders such as IBS.

The present invention therefore provides, in a first aspect, a compoundof formula (I) or a salt thereof: ##STR1## wherein: P represents phenyl,a quinoline or isoquinoline residue, or a 5-membered or 6-memberedaromatic heterocyclic ring containing up to three heteroatoms selectedfrom nitrogen, oxygen or sulphur;

X and Y are independently selected from oxygen, sulphur, carbon,nitrogen, C═O, CH, CH₂ or NR⁴ where R⁴ is hydrogen or C₁₋₆ alkyl;

Z is carbon, nitrogen or CH and the dotted lines represent optionaldouble bonds;

R¹ is hydrogen, C₁₋₆ alkyl, halogen, CF₃, NR⁷ R⁸ or OR⁹ where R⁷, R⁸ andR⁹ are independently hydrogen or C₁₋₆ alkyl;

R² is hydrogen or C₁₋₆ alkyl;

n is 0 to 3; and

R³ groups are independently C₁₋₆ alkyl optionally substituted by one ormore halogen atoms, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₆ alkyl, C₁₋₆ alkylthio, C₃₋₆ cycloalkylthio, C₃₋₆cycloalkylC₁₋₆ alkylthio, halogen, nitro, CF₃, OCF₃, SCF₃, SO₂ CF₃, SO₂F, formyl, C₂₋₆ alkanoyl, cyano, phenyl or thienyl optionallysubstituted by C₁₋₆ alkyl, halogen, CF₃, NR⁷ R⁸ or OR⁹ where R⁷, R⁸ andR⁹ are independently hydrogen or C₁₋₆ alkyl, or R³ is NR⁷ R⁸, CONR⁷ R⁸,or OR⁹ where R⁷, R⁸ and R⁹ are as defined for R¹, CO₂ R¹⁰ where R¹⁰ ishydrogen or C₁₋₆ alkyl, provided that:

when X and Y are both CH₂, Z is other than nitrogen,

when X, Y and Z form part of an indole ring, n is not zero.

C₁₋₆ Alkyl groups, whether alone or as part of another group, may bestraight chain or branched.

The amide moiety can be attached to a carbon or any available nitrogenatom of the ring P, preferably it is attached to a carbon atom. Suitablemoieties when the ring P is a 5-membered aromatic heterocyclic ringinclude isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl. Suitablemoieties when the ring P is a 6-membered aromatic heterocyclic ringinclude, for example, pyridyl, pyrimidyl or pyrazinyl. When P isquinoline, or an isoquinoline residue, the amide moiety can be attachedat any position of the ring, preferably to the 4- or 5-position.Preferably P is 3-pyridyl, in particular 3-pyridyl.

Suitably X and Y are independently selected from oxygen, sulphur,carbon, nitrogen, C═O, CH, CH₂ or NR⁴ where R⁴ is hydrogen or C₁₋₆ alkyland Z is selected from carbon, CH or nitrogen such that X, Y and Ztogether with the phenyl group to which they are attached form a 5,6bicyclic ring system. Examples of such ring systems includebenzothiophene, benzofuran, indene and indole. Preferably X is oxygen,sulphur or NR⁴, Z is carbon and Y is CH, i.e. Z-Y is a C═CH group suchthat X, Y and Z together with the phenyl group to which they areattached form part of a benzofuran, benzothiophene or indole ring.

Preferably R¹ is hydrogen.

Preferably R² is hydrogen.

Suitably R³ groups are independently C₁₋₆ alkyl optionally substitutedby one or more halogen atoms, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₆ alkylthio, C₃₋₆cycloalkylthio, C₃₋₆ cycloalkylC₁₋₆ alkylthio, halogen, nitro, CF₃,OCF₃, SCF₃, SO₂ CF₃, SO₂ F, formyl, C₂₋₆ alkanoyl, cyano, phenyl orthienyl optionally substituted by C₁₋₆ alkyl, halogen, CF₃, NR⁷ R⁸ orOR⁹ where R⁷, R⁸ and R⁹ are independently hydrogen or C₁₋₆ alkyl, or R³is NR⁷ R⁸, CONR⁷ R⁸, or OR⁹ where R⁷, R⁸ and R⁹ are as defined for R¹,CO₂ R¹⁰ where R¹⁰ is hydrogen or C₁₋₆ alkyl. When two adjacent R³ groupstogether form a 5-membered heterocyclic ring examples of such ringsinclude thienyl, furyl and pyrrollyl rings. When n is greater than 1 theresulting R³ groups can be the same or different. Preferably n is 2.Preferably an indoline, benzofuran or benzothiophene ring isdisubstituted in the 5- and 6-positions. Preferably the 5-position issubstituted by halogen or trifluoromethyl and the 6-position issubstituted by C₁₋₆ alkyl such as methyl or C₁₋₆ alkoxy such as methoxy,or C₁₋₆ alkylthio such as methylthio.

Particular compounds of the invention include:

5-Bromo-6-methoxy-N-(3-pyridyl)benzo- b!thiophene-3-carboxamide,

6-Methoxy-N-(3-pyridyl)-5-trifluoromethylbenzob!thiophene-3-carboxamide,

5-Bromo-6-methoxy-N-(3-pyridyl)benzo- b!furan-3-carboxamide,

6-Methoxy-N-(3-pyridyl)-5-trifluoromethylbenzo b!furan-3-carboxamide,

5-Bromo-6-methoxy-N-(3-pyridyl)indole-3-carboxamide,

6-Methoxy-1-methyl-N-(3-pyridyl)-5-trifluoromethylindole-3-carboxamide,

5-chloro-6-methyl-N-(3-pyridyl)benzothiophene-3-carboxamide,

5-Thiomethyl-6-trifluoromethyl-1-(3-pyridylcarbamoyl)-indole, andpharmaceutically acceptable salts thereof.

The compounds of the formula (I) can form acid addition salts withacids, such as conventional pharmaceutically acceptable acids, forexample maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulphonicacids.

Certain compounds of formula (I) may also form N-oxides or solvates suchas hydrates, and the invention also extends to these forms. Whenreferred to herein, it is understood that the term `compound of formula(I)` also includes these forms.

Certain compounds of formula (I) are capable of existing instereoisomeric forms including enantiomers and the invention extends toeach of these stereoisomeric forms and to mixtures thereof includingracemates. The different stereoisomeric forms may be separated one fromthe other by the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis. The invention also extends toany tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

the coupling of a compound of formula (II); ##STR2## with a compound offormula (III): ##STR3## wherein n, X, Y, Z and P are as defined informula (I), A and B contain the appropriate functional group(s)necessary to form the moiety --NR^(2') CO when coupled, the variablesR^(1'), R^(2') and R^(3') are R¹, R², and R³ respectively, as defined informula (I), or groups convertible thereto, and thereafter optionallyand as necessary and in any appropriate order, converting any R^(1'),R^(2') and R^(3'), when other than R¹, R² and R³ respectively to R¹, R²and R³, interconverting R¹, R² and R³ and forming a pharmaceuticallyacceptable salt thereof.

Preferably A is --NHR^(2') and B is COL wherein R^(2') is as definedabove and L is a leaving group. Such compounds can be reacted usingstandard chemistry. Examples of suitable compounds of formula (III)include acyl halides in which the leaving group L is halogen such aschloro. Activated compounds of formula (III) can also be prepared byreaction of the corresponding carboxylic acid with a coupling reagentsuch as carbonyldiimidazole, dicyclohexylcarbodiimide ordiphenylphosphoryl azide.

R³ groups can be introduced at any suitable stage in the process,preferably R³ groups are introduced at an early stage in the process. Itshould be appreciated that it is preferred that all groups R¹ to R³ areintroduced before coupling compounds of formula (II) and (III).

Suitable examples of groups R^(1'), R^(2') and R^(3') which areconvertible to R¹, R² and R³ alkyl groups respectively, include acylgroups which are introduced conventionally and may be converted to thecorresponding alkyl group by conventional reduction, such as usingsodium borohydride in an inert solvent followed by hydrogenolysis in aninert solvent. Hydrogen substituents may be obtained from alkoxycarbonylgroups which may be converted to hydrogen by hydrolysis anddecarboxylation. When R³ is hydroxy it is preferably protected in thecompound of formula (II) as, for example, benzyl which is removed byhydrogenation.

Suitable examples of a group R^(2') which are convertible to R², includealkoxycarbonyl and benzyl or para-methoxybenzyl which are converted tothe group where R² is hydrogen using conventional conditions.

Interconversions of R¹, R² and R³ are carried out by conventionalprocedures. For example R¹ halo and R³ halo may be introduced byselective halogenation of the ring P or the benzene ring of the indolinegroup using conventional conditions. It should be appreciated that itmay be necessary to protect any R¹ to R³ hydrogen variables which arenot required to be interconverted.

Suitable protecting groups and methods for their attachment and removalare conventional in the art of organic chemistry, such as thosedescribed in Greene T. W. `Protective groups in organic synthesis` NewYork, Wiley (1981).

Compounds of formula (II) in which A is NHR^(2') are known compounds orcan be prepared analogously to known compounds. As mentioned above,compounds of formula (III) are prepared from the corresponding acids,that is to say, compounds of formula (IV): ##STR4## in which n, X, Y, Zand R^(3') are as defined in formula (III). Compounds of formula (IV)are either commercially available or may be prepared according to knownmethods or analogous to known methods. Novel intermediates of formula(III) also form part of the invention.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative. N-oxides may beformed conventionally by reaction with hydrogen peroxide orpercarboxylic acids.

Compounds of formula (I) and their pharmaceutically acceptable saltshave 5HT_(2B/2C) receptor antagonist activity and are believed to be ofpotential use fo the treatment or prophylasis of CNS disorders such asanxiety, depression, epilepsy, obsessive compulsive disorders, migraine,Alzheimers disease, sleep disorders, feeding disorders such as anorexiaand bulimia, panic attacks, withdrawal from drug abuse such as cocaine,ethanol, nicotine and benzodiazepines, schizophrenia, and also disordersassociated with spinal trauma and/or head injury such as hydrocephalus.Compounds of the invention are also expected to be of use in thetreatment of certain GI disorders such as IBS.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment or prophylaxis of the abovedisorders.

The invention further provides a method of treatment or prophylaxis ofthe above disorders, in mammals including humans, which comprisesadministering to the sufferer a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment or prophylaxis of theabove disorders.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusable solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. The compound, depending on thevehicle and concentration used, can be either suspended or dissolved inthe vehicle. In preparing solutions, the compound can be dissolved forinjection and filter sterilised before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspension in a sterilevehicle. Advantageously, a surfactant or wetting agent is included inthe composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration.

The dose of the compound used in the treatment of the aforementioneddisorders will vary in the usual way with the seriousness of thedisorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unitdoses may be administered more than once a day, for example two or threea day, so that the total daily dosage is in the range of about 0.5 to100 mg; and such therapy may extend for a number of weeks or months.

When administered in accordance with the invention, no unacceptabletoxicological effects are expected with the compounds of the invention.

The following Descriptions and Examples illustrate the preparation ofcompounds of the invention.

DESCRIPTION 1 3-Methoxy-4-bromoaniline (D1)

2-Bromo-5-nitroanisole (31 g, 134 mmoles) in methanol (700 ml) was addedto a mixture of iron powder (22.5 g, 400 mmoles), and ammonium chloride(33.5 g, 630 mmoles) in water (600 ml). The mixture was heated underreflux for 3 hrs. The mixture was allowed to cool and filtered. Thefiltrate was concentrated in vacuo and the residue partitioned betweenwater and dichloromethane. The organic phase was dried (Na₂ SO₄),filtered and evaporated to dryness to give the title compound (D1) (25g, 93%).

NMR (CDCl₃) δ: 3.60-3.75 (2H, br s), 3.81 (3H, s), 6.12-6.19 (1H, m),6.21 (1H, s), 7.23 (1H, d, J=8 Hz)

DESCRIPTION 2 3-Methoxy-4-bromobenzenethiol (D2)

3-Methoxy-4-bromoaniline (D1) (14.0 g, 69 mmoles) was diazotised inconcentrated hydrochloric acid/ice-water 50:50 (40 ml) by treating withsodium nitrite (5.0 g, 72 mmoles). The diazonium salt was then addedvery slowly to a solution of ethyl potassium xanthate (12.2 g, 76mmoles) in water (20 ml) at 55° C. The resulting xanthate ester wassubjected to base hydrolysis followed by acid-base extraction to givethe title compound (D2) (8.1 g, 53%)*

NMR (CDCl₃) δ: 3.50 (1H, s), 3.85 (3H, s), 6.71-6.82 (2H, m), 7.38 (1H,d, J=8 Hz.

* Detailed procedure: D. S. Tarbell, D. K. Fukushima, Organic Synthesis,Collective Volume III, p809.

DESCRIPTION 3 Ethyl 3-(3-methoxy-4-bromophenylthio)-2-oxopropanoate (D3)

3-Methoxy-4-bromobenzenethiol (D2) (9.6 g, 44 mmoles) in pyridine (30ml) was treated with ethyl bromopyruvate (5.9 ml, 46 mmoles) and stirredat room temperature for 1 hr. Dilute hydrochloric acid (100 ml) wasadded and the product extracted into diethyl ether. The organics werewashed with dilute hydrochloric acid then brine and dried (Na₂ SO₄).Evaporation of the solvent followed by flash chromatography on TLCsilica gel eluting with dichloromethane gave the title compound (D3)(3.7 g, 25%).

NMR (CDCl₃) δ: 1.25-1.45 (3H, m), 3.90 (3H, s), 4.25-4.40 (2H, m),6.81-6.95 (2H, m), 7.41 (1H, d, J=8 Hz)

DESCRIPTION 4 Ethyl 5-bromo-6-methoxybenzo b!thiophene-3-carboxylate(D4)

Ethyl 3-(3-methoxy-4-bromophenylthio)-2-oxopropanoate (D3) (3.7 g, 11mmoles) in chlorobenzene (25 ml) was treated with phosphorus pentoxide(11.1 g, 78 mmoles) and 85% phosphoric acid (5.5 ml). The mixture washeated under reflux for 6 hrs. The mixture was allowed to cool and thenpartitioned between water (150 ml) and dichloromethane. The organicswere washed several times with water then dried (Na₂ SO₄). Evaporationto dryness followed by flash chromatography on TLC silica gel elutingwith dichloromethane/60-80 petrol-ether 1:1 gave the title compound (D4)(0.94 g, 27%).

NMR (CDCl₃) δ: 1.42 (3H, t, J=8 Hz), 3.95 (3H, s), 4.40 (2H, q, J=8 Hz),7.30 (1H, s), 8.20 (1H, s), 8.78 (1H, s).

DESCRIPTION 5 5-Bromo-6-methoxybenzo b!thiophene-3-carboxylic acid (D5)

Ethyl 5-bromo-6-methoxybenzo b!thiophene-3-carboxylate (D4) (0.42 g,0.0013 mole) in ethanol (20 ml) and water (5 ml) was treated with sodiumhydroxide powder (0.14 g, 0.0035 mole). The reaction mixture was heatedunder reflux for 2 hours and stirred at ambient temperature for 16hours. The solvent was removed in vacuo and the residue diluted withwater (25 ml), acidified with 5N hydrochloric acid, extracted into ethylacetate, dried (Na₂ SO₄) and evaporated in vacuo to afford the titlecompound (0.36 g, 93%) as a beige solid.

¹ H NMR (200 MHz; D⁶ DMSO); δ: 3.08-3.60 (1H, br s), 3.93 (3H, s), 7.88(1H, s), 8.52 (1H, s), 8.64 (1H, s).

DESCRIPTION 6 Ethyl 5-trifluoromethyl-6-methoxybenzob!thiophene-3-carboxylate (D6)

Ethyl-5-bromo-6-methoxybenzo b!thiophene-3-carboxylate (D4) (0.81 g, 3mmoles) in dry dimethylformamide (20 ml) and toluene (10 ml) was treatedwith potassium trifluoroacetate (0.78 g, 6 mmoles) and copper (I) iodide(0.98 g, 6 mmoles). The mixture was heated under reflux for 1 hr using aDean-Stark trap to collect the toluene. The mixture was cooled andpoured into water (150 ml) and extracted with diethyl ether. Theresulting emulsion was filtered through kieselguhr. The combined organicextracts were washed several times with water then dried (Na₂ SO₄).Flash chromatography on TLC silica gel eluting withdichloromethane/60-80 petrol ether 1:1 gave the title compound (D6) (0.5g, 64%)

NMR (CDCl₃) δ: 1.45 (3H, t, J=8 Hz), 3.95 (3H, s), 4.40 (2H, q, J=8 Hz),7.40 (1H, s), 8.25 (1H, s), 8.8 (1H, s)

DESCRIPTION 7 5-Trifluoromethyl-6-methoxybenzo b!thiophene-3-carboxylicacid (D7)

Ethyl 5-trifluoromethyl-6-methoxybenzo b!thiophene-3-carboxylate (D6)(0.5 g, 2 mmoles) was treated with sodium hydroxide as in the method ofdescription 5 to give the title compound (D7) (0.42 g, 92%)

NMR (DMSO) δ: 3.95 (3H, s), 8.0 (1H, s), 8.58 (1H, s), 8.21 (1H, s),13.11-13.21 (1H, br s)

DESCRIPTION 8 3-Methoxy-4-bromophenol (D8)

3-Methoxy-4-bromoaniline (D1) (10.0 g, 49 mmoles) in water (60 ml) andconcentrated sulphuric acid (30 ml) was treated with a solution ofsodium nitrite (3.4 g, 49 mmoles) in water (15 ml) dropwise keeping thetemperature below 5° C. The resulting slurry was then added slowly to amixture of water (60 ml) and concentrated sulphuric acid (30 ml) at 80°C. and stirred at this temperature for 3 hrs. The mixture was cooled andextracted with dichloromethane (2×200 ml). The organics were thenextracted with 2N sodium hydroxide solutions (2×100 ml). The aqueous waswashed with more dichloromethane (2×200 ml) then acidified to pH 1.Extraction with dichloromethane, drying (Na₂ SO₄) and evaporation todryness gave the title compound (D8) (6.95 g, 69%).

NMR (CDCl₃) δ: 3.85 (3H, s), 4.75-4.95 (1H, br s), 6.29-6.35 (1H, m),6.45 (1H, s), 7.35 (1H, d, J=8 Hz).

DESCRIPTION 9 Ethyl 3-methoxy-4-bromophenoxyacetate (D9)

3-Methoxy-4-bromophenol D8 (6.95 g, 34 mmoles) in dry dimethylformamide(100 ml) at 0° C. was treated with sodium hydride (80% dispersion inoil) (1.13 g, 37 mmoles). After 30 mins ethyl bromoacetate (3.8 ml, 34mmoles) was added and the mixture allowed to warm to room temperatureover 1 hr. The mixture was concentrated in vacuo and the residuepartitioned between water and diethyl ether. The organic layer waswashed several times with water and then dried (Na₂ SO₄) and evaporatedto dryness. Flash chromatography on TLC silica gel eluting withdichloromethane gave the title compound (D9) (7.43 g, 75%)

NMR (CDCl₃) δ: 1.30 (3H, t, J=8 Hz), 3.85 (3H, s), 4.28 (2H, q, J=8 Hz),6.28-6.32 (1H, m), 6.58 (1H, s), 7.40 (1H, d, J=10 Hz)

DESCRIPTION 10 Diethyl-3-methoxy-4-bromophenoxyoxalate (D10)

Diethyl oxalate (2.8 ml, 20 mmoles) was added to a suspension of sodiumethoxide (1.48 g, 21 mmoles) in dry diethyl ether (30 ml) and stirred atroom temperature for 15 mins. A solution ofethyl-3-methoxy-4-bromophenoxyacetate (D9) (6.0 g, 20 mmoles) in diethylether (30 ml) was then added dropwise. The mixture was stirred at roomtemperature for 18 hrs then washed with 1N hydrochloric acid (2×100 ml),water (100 ml), brine (100 ml) then dried (Na₂ SO₄). Evaporation ofsolvent gave the title compound (D10) (7.84 g, 97%).

NMR (CDCI₃) δ: 1.20-1.45 (6H, m), 3.80 (3H, s), 4.20-4.45 (4H, m),6.31-6.42 (1H, m), 6.55-6.68 (1H, m), 7.37-7.45 (1H, m)

DESCRIPTION 11 Diethyl 5-bromo-6-methoxybenzo b!furan-2,3-dicarboxylate(D11)

Diethyl 3-methoxy-4-bromophenoxyoxalacetate (D10) (7.8 g, 20 mmoles) wasstirred with concentrated sulphuric acid (50 ml) for 30 mins. Themixture was then poured into ice water (500 ml) and extracted withdiethyl ether (250 ml). The organics were washed with saturated aqueoussodium bicarbonate, dried (Na₂ SO₄) and evaporated to dryness. Flashchromatography on TLC silica gel eluting with dichloromethane gave thetitle compound (D11) (3.29 g, 44%)

NMR (CDCl₃) δ: 1.37-1.50 (6H, m), 3.90 (3H, s), 4.39-4.53 (4H, m), 7.05(1H, s), 8.07 (1H, s)

DESCRIPTION 12 5-Bromo-6-methoxybenzo b!furan-2,3-dicarboxylic acid(D12)

Diethyl 5-bromo-6-methoxybenzo b!furan-2,3-dicarboxylate (D11) (1.26 g,3.4 mmoles) in ethanol (20 ml) and water (5 ml) was treated with 20%sodium hydroxide solution (5 ml) and heated under reflux for 3 hrs. Themixture was cooled and the ethanol removed in vacuo. The mixture wasacidified to pH1 with hydrochloric acid. Filtration of the solid anddrying gave the title compound (D12) (0.91 g, 85%)

NMR (DMSO-d₆) δ: 3.90 (3H, s), 7.50 (1H, s), 7.90-8.80 (3H including 2H,br s and 8.25 (1H, s))

DESCRIPTION 13 5-Bromo-6-methoxybenzo b!furan-3-carboxylic acid (D13)

5-Bromo-6-methoxybenzo b!furan-2,3-dicarboxylic acid (D12) (0.85 g, 2.7mmoles) was heated to its melting point (˜270° C.) for 15 mins (CO₂evolution). The mixture was allowed to cool and the resulting blackresidue extracted with ethyl acetate. The organic solution was thenfiltered and the filtrate evaporated to dryness to give the titlecompound (D13) (0.65 g, 89%)

NMR (DMSO-d₆) δ: 3.90 (3H, s), 7.51 (1H, s), 8.02 (1H, s), 8.60 (1H, s).

DESCRIPTION 14 Ethyl 5-bromo-6-methoxybenzo b!furan-3-carboxylate (D14)

5-Bromo-6-methoxybenzo b!furan-3-carboxylic acid (D13) (0.27 g, 1 mmole)was heated under reflux for 1 hr in thionyl chloride. Cooling andevaporating to dryness gave the acid chloride which was treated withethanol (10 ml) and triethylamine (1 ml). After 1 hr the mixture wasevaporated to dryness and the residue partitioned between water anddichloromethane. The organic layer was dried (Na₂ SO₄) and evaporated todryness. Flash chromatography on TLC silica gel eluting withdichloromethane/60-80 petrol ether 50:50 gave the title compound (D14)(0.077 g, 26%)

NMR (CDCl₃) δ: 1.40 (3H, t, J=8 Hz), 3.90 (3H, s), 4.39 (2H, q, J=8 Hz),7.03 (1H, s), 8.13 (1H, s), 8.19 (1H, s)

DESCRIPTION 15 Ethyl 5-trifluoromethyl-6-methoxybenzob!furan-3-carboxylate (D15)

Ethyl-5-bromo-6-methoxybenzo b!furan-3-carboxylate (D14) (0.077 g, 0.3mmoles) was converted to the title compound (D15) as in the method ofdescription 6 (0.028 g, 38%)

NMR (CDCl₃) δ: 1.40 (3H, t, J=8 Hz), 3.92 (3H, s), 4.40 (2H, q, J=8 Hz),7.10 (1H, s), 8.20 (1H, s), 8.28 (1H, s).

DESCRIPTION 16 5-Trifluoromethyl-6-methoxybenzo b!furan-3-carboxylicacid (D16)

Ethyl 5-trifluoromethyl-6-methoxybenzo b!furan-3-carboxylate (D15)(0.028, 0.1 mmoles) was hydrolysed to the title compound (D16) as in themethod of description 5 (0.022 g, 90%)

DESCRIPTION 17 4-Bromo-3-methoxy-N-methylsulphonylanilide (D17)

Methanesulphonyl chloride (22.4 ml, 289 mmol) was added dropwise to asolution of aniline (D1, 56.1 g, 277.7 mmol) and pyridine (23.1 ml,277.7 mmol) in dry dichloromethane (600 ml) at 0° C. The mixture wasstirred overnight, then washed with water three times, dried andconcentrated to crystallise the product. A further crop was obtained byaddition of petrol to the mother liquor and further concentration. Thetwo crops were combined to give the title compound (68.0 g, 87%) mp121-4° C.

NMR (CDCl₃) δ: 3.03 (3H, s), 3.91 (3H, s), 6.79 (1H, dd, J=7,2), 6.89(1H, d, J=2), 7.49 (1H, d, J=7)

DESCRIPTION 18 4-Bromo-N-(2,2-diethoxyethyl)-3-methoxy-N-methylsulphonylanilide (D18)

A solution of sulphonylanilide (D17, 68.0 g, 243 mmol) indimethyl-formamide (350 ml) was added over 40 min to a suspension ofsodium hydride (80% in oil, 8.1 g, 269.5 mmol) in dimethylformamide (50ml) at 0° C. After 30 min, when evolution of hydrogen had ceased,(2,2-diethoxyethyl)trifluoromethanesulphonate (77.8 g, 292.5 mmol) wasadded as a steady stream. After 6h at room temperature furtherquantities of sodium hydride (0.8 g) and trifluoromethanesulphonate (8g) were added, and stirring was continued overnight. The mixture wasthen partially evaporated, diluted with water and extracted withtoluene. The organic extract was washed well with water and brine, driedand evaporated. The residue was recrystallised twice fromdichloromethane/petrol to give the title compound (39 g, 40.5%), mp.70-72° C.

NMR (CDCl₃) δ: 1.18 (3H, t, J=7), 2.97 (3H, s), 3.51 (2H, m), 3.67 (2H,m), 3.75 (2H, d, J=6), 3.90 (3H, s), 4.41 (1H, t, J=6), 6.83 (1H, dd,J=7, 2), 6.97 (1H, d, J=2), 7.54 (1H, d, J=7)

DESCRIPTION 19 5-Bromo-6-methoxy-1-methylsulphonylindole (D19)

A solution of titanium tetrachloride in toluene (138 ml of 1M solutiondiluted with 750 ml toluene) was added slowly to a solution ofdiethoxyethyl anilide (D18, 39 g, 98.4 mmol) in toluene (2.0 L) at 0° C.Internal temperature remained below 5° C. during addition. The mixturewas then heated until reflux began, maintained at reflux for 10 min,then cooled, washed with sat. sodium bicarbonate solution, dilutehydrochloric acid and water, dried and evaporated. The residue wasrecrystallised from ether. The mother liquor was chromatographed onsilica gel eluted with dichloromethane and eluted material wasrecrystallised from ether to give a second crop. The two crops werecombined to give the title compound (21.2 g, 71%), mp. 126-129° C.

NMR (CDCl₃) δ: 3.09 (3H, s), 3.98 (3H, s), 6.61 (1H, d, J=3), 7.34 (1H,d, J=3), 7.48 (1H, s), 7.79 (1H, s)

DESCRIPTION 20 5-Bromo-6-methoxy indole (D20)

The 1-methylsulphonylindole (D19, 21.2 g, 69.7 mmol) was heated underreflux in a mixture of 10% aqueous sodium hydroxide solution (170 ml)and ethanol (1.0 L) for 1.5 h. The mixture was evaporated almost todryness, and the residue was dissolved in ethyl acetate and washed withwater. The organic phase was dried and evaporated to give the titlecompound (15.65 g, 99%), mp 110-111° C.

NMR (CDCl₃) δ: 3.90 (3H, s), 6.43 (1H, m), 6.91 (1H, s), 7.10 (1H, m),7.80 (1H, s), 8.18 (1H, broad)

DESCRIPTION 21 5-Bromo-6-methoxy-3-trichloroacetyl indole (D21)

Trichloroacetyl chloride (8.5 ml, 76.1 mmol) was added to a solution ofpyridine (6.1 ml, 76.1 mmol) in dry 1,4-dioxan (70 ml). After a fewminutes of stirring, a solution of indole (D20, 15.65 g, 69.2 mmol) in1,4-dioxan (70 ml) was added slowly. The mixture was stirred for 24 h atroom temperature, then poured into water. The precipitate was filteredoff and washed with water, then recrystallised from ethanol/water togive the title compound (14.19 g, 55%), mp. 185-190° C.

NMR (CDCl₃ /CD₃ OD) δ: 3.93 (3H, s), 6.97 (1H, s), 8.24 (1H, s), 8.58(1H, s)

DESCRIPTION 22 5-Bromo-6-methoxyindole-3-carboxylic acid (D22)

The trichloroacetylindole (D21, 1.48 g, 4 mmol) was heated in a mixtureof 10% aqueous potassium hydroxide (3 ml) and tetrahydrofuran (15 ml) at40-50° C. over three nights. The mixture was poured into water andextracted with ether. The ethereal phase was re-extracted with dil.potassium hydroxide solution, and the combined aqueous phases wereacidified with 10% aq. hydrochloric acid and extracted withdichloromethane/methanol. This extract was dried and evaporated to givethe title compound (0.74 g, 68.5%)

NMR (CD₃ OD) δ: 3.90 (3H, s), 7.07 (1H, s), 7.87 (1H, s), 8.19 (1H, s)

DESCRIPTION 23 5-Bromo-6-methoxy-1methyl-3-trichloroacetylindole (D23)

The trichloroacetylindole (D21, 1.86 g, 5 mmol) was added in smallportions to a suspension of sodium hydride (80% in oil, 0.165 g, 5.5mmol) in dry dimethylformamide (20 ml). After stirring at roomtemperature for 20 min., methyl iodide (0.34 ml, 5.5 mmol) was added.After stirring for 1 h, the mixture was partially evaporated and theresidue was poured into water. The precipitate was filtered off, washedwith water and dried to give the title compound (1.75 g, 91%)

NMR (CDCl₃) δ: 3.88 (3H, s), 3.98 (3H, s), 6.80 (1H, s), 8.09 (1H, s),8.60 (1H, s).

DESCRIPTION 24 Methyl 5-bromo-6-methoxy-1-methylindole-3-carboxylate(D24)

The trichloroacetylindole (D23, 1.73 g, 4.5 mmol) was heated underreflux in methanol (20 ml) containing 1 drop of 60% aqueous potassiumhydroxide for 45 min. The mixture was then evaporated and the residuewas slurried with water. The solid was filtered off and washed withwater, then chromatographed on silica gel eluted with 0-2%methanol/dichloromethane to give the title compound (1.03 g, 77%)

NMR (CDCl₃) δ: 3.79 (3H, s), 3.91 (3H, s), 3.96 (3H, s), 6.76 (1H, s),7.67 (1H, s), 8.30 (1H, s)

DESCRIPTION 25 Methyl6-methoxy-1-methyl-5-trifluoromethylindole-3-carboxylate (D25)

A mixture of methyl ester (D24, 1.01 g, 3.4 mmol), potassiumtrifluoroacetate (1.04 g, 6.8 mmol) and copper (I) iodide (1.27 g, 6.8mmol) in toluene (10 ml) and dimethylformamide (20 ml) was heated todistil off toluene. The mixture was then heated at 148-150° C.(internal) for 2 h. A further quantity of potassium trifluoroacetate(0.5 g) was added and heating continued for 2 h. The mixture was thenevaporated and the residue was extracted with dichloromethane/methanol.The extract was filtered, washed with water, dried and evaporated. Theresidue was recrystallised from dichloromethane/petrol to give the titlecompound (0.67 g, 69%), mp. 166-170° C.

NMR (CDCl₃) δ: 3.81 (3H, s), 3.92 (3H, s), 3.97 (3H, s), 6.81 (1H, s),7.73 (1H, s), 8.37 (1H, s).

DESCRIPTION 26 6-Methoxy-1-methyl-5-trifluoromethylindole-3-carboxylicacid (D26)

The trifluoromethylindole ester (D25, 0.67 g, 2.33 mmol) was heatedunder reflux in a mixture of 10% aqueous sodium hydroxide (5 ml) andmethanol (10 ml) for 30 min. The mixture was then diluted with water todissolve all solid and extracted with dichloromethane. The aqueous phasewas acidified with 5M hydrochloric acid and the precipitate was filteredoff and dried to give the title compound (0.56 g, 88%), mp. >247° C.(decomp.)

NMR (d₆ -DMSO) δ: 3.86 (3H, s), 3.94 (3H, s), 7.34 (1H, s), 8.03 (1H,s), 8.22 (1H,s)

DESCRIPTION 27 5-Chloro-6-methylbenzo b! thiophene (D27)

The title compound was prepared by adding(3-methyl-4-chlorophenylthio)acetaldehyde diethyl acetal topolyphosphoric acid under reduced pressure (1.5 mm Hg).* This gave 1.8 gof a mixture of the title compound (D27) and 4-methyl-5-chlorobenzob!thiophene in a 60:40 ratio.

NMR (CDCl₃) δ: 2.40 (3H, s), 7.12 (1H, d, J=6), 7.29 (1H, d, J=6), 7.61(1H, s), 7.70 (1H, s)+peaks for undesired isomer.

DESCRIPTION 28 5-Chloro-6-methylbenzo b! thiophene-3-carboxylic acid(D28)

Friedel-Crafts acylation of the mixture containing5-chloro-6-methylbenzo b! thiophene (D27) and 4-methyl-5-chlorobenzo b!thiophene with trichloroacetyl chloride/aluminium chloride followed bybasic hydrolysis* gave the title compound (D28) (0.09 g, 24%)

NMR (DMSO-d₆) δ: 2.40 (3H, s), 7.89 (1H, s), 8.00 (1H, s), 8.82 (1H, s).

EXAMPLE 1 5-Bromo-6-methoxy-N-(3-pyridyl)benzo-b!thiophene-3-carboxamide (E1)

5-Bromo-6-methoxybenzo b!thiophene-3-carboxylic acid (D5) (0.36 g,0.0013 mole) and thionyl chloride (20 ml) were heated under reflux for 1hour, after which the reaction mixture was cooled to ambient temperatureand evaporated in vacuo. The resulting acid chloride was dissolved indry dichloromethane (30 ml) and acetonitrile (10 ml) under argon.3-Aminopyridine (0.12 g, 0.0013 mole) was added and the reaction mixturestirred at ambient temperature for 16 hours. The solvent was removed invacuo and the resulting solid basified with 10% sodium hydroxidesolution, extracted into dichloromethane, dried (Na₂ SO₄) and evaporatedin vacuo. The resulting solid was recrystallised from ethylacetate/methanol to afford the title compound (0.11 g, 23%) as a beigesolid.

¹ H NMR (270 MHz; D⁶ DMSO) δ: 3.93 (3H, s), 7.42 (1H, q), 7.89 (1H, s),8.20 (1H, dt), 8.34 (1H, d), 8.56 (1H, s), 8.64 (1H, s), 8.93 (1H, s),10.55 (1H, s)

EXAMPLE 2 6-Methoxy-N-(3-pyridyl)-5-trifluoromethylbenzob!thiophene-3-carboxamide hydrochloride salt (E2)

5-Trifluoromethyl-6-methoxybenzo b!thiophene-3-carboxylic acid (D7)(0.39 g, 1.4 mmoles) was converted to the title compound as in themethod of example 1 isolating as the hydrochloride salt afterrecrystallising from methanol. (E2) (0.33 g, 58%) m.p. >270° C.

NMR (DMSO-d₆) δ: 3.97 (3H, s), 7.91-7.99 (1H, m), 8.03 (1H, s), 8.62(1H, d, J=6 Hz), 8.72 (1H, s), 8.81 (1H, d, J=6 Hz), 9.01 (1H, s), 9.41(1H, s), 11.51 (1H, s), M⁺ =352; C₁₆ H₁₁ N₂ O₂ SF₃ requires 352

EXAMPLE 3 5-Bromo-6-methoxy-N-(3-pyridyl)benzo b!furan-3-carboxamide(E3)

5-Bromo-6-methoxybenzo b!furan-3-carboxylic acid (D13) (0.4 g, 1.4moles) was converted to the title compound (E3) as in the method ofexample 1 (0.29 g, 58%) m.p. 210-212° C.

NMR (DMSO-d₆) δ: 3.91 (3H, s), 7.38-7.42 (1H, m), 7.52 (1H, s),8.10-8.17 (1H, m), 8.20 (1H, s), 8.29-8.33 (1H, m), 8.70 (1H, s), 8.88(1H, s). M⁺ =346 and 348, C₁₅ H₁₁ N₂ O₃ Br requires 346 and 348

EXAMPLE 4 6-Methoxy-N-(3-pyridyl)-5-trifluoromethylbenzob!furan-3-carboxamide (E4)

5-Trifluoromethyl-6-methoxybenzo b!furan-3-carboxylic acid (D16) (0.025g, 0.1 mmoles) was converted to the title compound as in the method ofexample 1 (0.025 g, 83%) mp. 219-221° C.

NMR (DMSO-d₆) δ: 3.95 (3H, s), 7.35-7.42 (1H, m), 7.65 (1H, s), 8.12(1H, d, J=8 Hz), 8.25-8.39 (2H, m), 8.80 (1H, s), 8.90 (1H, s)

EXAMPLE 5 5-Bromo-6-methoxy-N-(3-pyridyl)indole-3-carboxamide (E5)

To a solution of acid (D22, 0.86 g, 3.2 mmol) in dry tetrahydrofuran (30ml) was added oxalyl chloride (0.27 ml, 3.2 mmol) and dimethylformamide(3 drops). After stirring for 1 h at room temperature the mixture wasevaporated. Fresh tetrahydrofuran (30 ml) was added, followed by asolution of 3-aminopyridine (0.30 g, 3.2 mmol) and triethylamine (0.44ml, 3.2 mmol) in tetraydrofuran (10 ml). The mixture was stirred at roomtemperature overnight, then evaporated. The residue was dissolved indichloromethanelmethanol and this solution was washed with water,saturated aqueous potassium carbonate and brine, dried and evaporated.The crude product was chromatographed on silica gel eluted with 10%methanol/dichloromethane to give the title compound (0.29 g, 26%),mp. >250° C.

NMR (d₆ -DMSO) δ: 3.88 (3H, s), 7.15 (1H, s), 7.38 (1H, dd, J=7, 5),8.19 (1H, dm, J=7), 8.27 (2H, m), 8.33 (1H, s), 8.90 (1H, d, J=2), 9.96(1H, s), 11.77 (1H, s).

MS (EI) m/e=347 (M⁺)

EXAMPLE 66-Methoxy-1-methyl-N-(3-pyridyl)-5-trifluoromethylindole-3-carboxamide(E6)

This compound was prepared by the method of Example 5, from acid (D26,0.55 g, 2.0 mmol) and 3-aminopyridine (0.19 g, 2.0 mmol), with otherreagents and solvents in proportionate quantities. After addition of theaminopyridine, the mixture was stirred for 4 h at room temperature, thenpoured into water. The precipitate was filtered off, washed with waterand dried. The crude product was recrystallised fromdichloromethane/methanol to give the title compound (0.55 g, 79%),mp. >250° C.

NMR (d₆ -DMSO) δ: 3.92 (3H, s), 3.97 (3H, s), 7.39 (2H, m), 8.20 (1H, d,J=8), 8.28 (1H, d, J=5), 8.31 (1H, s), 8.45 (1H, s), 8.90 (1H, d, J=2),10.07 (1H, s); MS (EI) m/e=349 (M⁺)

EXAMPLE 7 5-Chloro-6-methyl-N-(3-pyridyl)benzo b!thiophene-3-carboxamide hydrochloride (E7)

5-Chloro-6-methylbenzo b! thiophene-3-carboxylic acid (D2) (0.09 g, 0.4mmoles) was treated with thionyl chloride (10 ml) and heated underreflux for 2 hrs. The mixture was evaporated to dryness and theresulting acid chloride was re-dissolved in dichloromethane (10 ml) andtreated with 3-acinopyridine (0.038 g, 0.4 mmoles). After 4hrs theprecipitate was filtered off. Recrystallisation from methanol gave thetitle compound (E1) (0.04 g, 30%) m.p. 160-1° C.

NMR (DMSO-d₆) δ: 2.45 (3H, s), 7.73-7.81 (1H, m), 8.11 (1H, s),8.47-8.53 (3H, m), 8.80 (1H, s), 9.20 (1H, s), 11.01 (1H, s). Found M⁺302, 304; C₁₅ H₁₁ N₂ O5Cl requires 302, 304

EXAMPLE 8 5-Thiomethyl-6-trifluoromethyl-1-(3-pyridylcarbamoyl)-indole(E8)

A solution of 5-methylthio-1-(3-pyridylcarbamoyl)-6-trifluoromethylindoline (WO 95/01976) (500 mg, 1.4 mmol) in acetic acid (10 ml) underargon atmosphere was treated with manganese triacetate (415 mg, 1.53mmol) and heated under reflux for 4 days. Work-up of the solution(neutralisation of the solution with sodium bicarbonate solution,filtration and extraction of the aqueous into dichloromethane) affordeda mixture which was separated by HPLC to yield a green powder (20 mg).

¹ H NMR 250 MHz d⁶ -DMSO δ: 2.51 (s, 3H), 6.88 (d, 2H), 7.45 (m, 1H),7.84 (s, 1H), 8.09 (m, 1H), 8.26 (d, 1H), 8.38 (d, 1H), 8.60 (s, 1H),8.80 (m, 1H). Mass. spec. M⁺ m/z=351 (10%)

PHARMACOLOGICAL DATA ³ H!-mesulergine binding to rat or human 5-HT_(2C)clones expressed in 293 cells in vitro

Compounds were tested following the procedure outlined in WO 94/04533.

The compounds of examples 3 to 8 have pK_(i) values of at least 7.2

We claim:
 1. A compound of formula (I) or a salt thereof: ##STR5##wherein: P represents pyridyl;X and Y are independently selected fromoxygen, sulphur, nitrogen, CH, CH₂ or NR⁴ where R⁴ is hydrogen or C₁₋₆alkyl; Z is carbon, nitrogen or CH and the dotted lines representoptional double bonds; R¹ is hydrogen, C₁₋₆ alkyl, halogen, CF₃, NR⁷ R⁸or OR⁹ where R⁷, R⁸ and R⁹ are independently hydrogen or C₁₋₆ alkyl; R²is hydrogen or C₁₋₆ alkyl; n is 0 to 3; and R³ groups are independentlyC₁₋₆ alkyl optionally substituted by one or more halogen atoms; C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₆alkylthio, C₃₋₆ cycloalkylthio, C₃₋₆ cycloalkylC₁₋₆ alkylthio, halogen,nitro, CF₃, OCF₃, SCF₃, SO₂ CF₃, SO₂ F, formyl, C₂₋₆ alkanoyl, cyano,phenyl or thienyl optionally substituted by C₁₋₆ alkyl, halogen, CF₃,NR⁷ R⁸ or OR⁹ where R⁷, R⁸ and R⁹ are independently hydrogen or C₁₋₆alkyl, or R³ is NR⁷ R⁸, CONR⁷ R⁸, or OR⁹ where R⁷, R⁸ and R⁹ are asdefined for R¹, CO₂ R¹⁰ where R¹⁰ is hydrogen or C₁₋₆ alkyl, providedthat:when X and Y are both CH₂, Z is other than nitrogen, when X, Y andZ form part of an indole ring, n is not zero.
 2. A compound according toclaim 1 in which R¹ is hydrogen.
 3. A compound according to claim 1 inwhich R² is hydrogen.
 4. A compound according to claim 1 in which n is2.
 5. A compound according to claim 1 whichis:5-Bromo-6-methoxy-N-(3-pyridyl)benzo- b!thiophene-3-carboxamide,6-Methoxy-N-(3-pyridyl)-5-trfuoromethylbenzo b!thiophene-3-carboxamide,5-Bromo-6-methoxy-N-(3-pyridyl)benzo- b!furan-3-carboxamide,6-Methoxy-N-(3-pyridyl)-5-trifluoromethylbenzo b!furan-3-carboxamide,5-Bromo-6-methoxy-N-(3-pyridyl)indole-3-carboxamide,6-Methoxy-1-methyl-N-(3-pyridyl)-5-trifluoromethylindole-3-carboxamide,5-chloro-6-methyl-N-(3-pyridyl)benzothiophene-3-carboxamide,5-Thiomethyl-6-trifluoromethyl-1-(3-pyridylcarbamoyl)-indole, andpharmaceutically acceptable salts thereof.
 6. A pharmaceuticalcomposition which comprises a compound according to claim 1 and apharmaceutically acceptable carrier or excipient.
 7. A method oftreatment of CNS and IBS which comprises administering to a sufferer atherapeutically effective amount of a compound of formula (I) as definedin claim 1 or a pharmaceutically acceptable salt thereof.
 8. A processfor the preparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, which process comprises:the coupling of acompound of formula (II); ##STR6## with a compound of formula (III);##STR7## wherein n, X, Y, Z and P are as defined in formula (I), A is agroup NHR² and B is COL where R¹, R², and R³ are as defined in formula(I) and L is a leaving group; and thereafter forming a pharmaceuticallyacceptable salt thereof.